12-14661078-C-T

Variant names:

• chr12-14661078-C-T
• rs112926992
• NM_004963.4:c.1283-16G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_004963.4(GUCY2C):​c.1283-16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,536,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: GUCY2C NM_004963.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.570
• Publications: 1 publications found

Genes affected

GUCY2C (HGNC:4688): (guanylate cyclase 2C) This gene encodes a transmembrane protein that functions as a receptor for endogenous peptides guanylin and uroguanylin, and the heat-stable E. coli enterotoxin. The encoded protein activates the cystic fibrosis transmembrane conductance regulator. Mutations in this gene are associated with familial diarrhea (autosomal dominant) and meconium ileus (autosomal recessive). [provided by RefSeq, Nov 2016]

GUCY2C Gene-Disease associations (from GenCC):

• congenital diarrhea 6

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• congenital sodium diarrhea

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-14661078-C-T is Benign according to our data. Variant chr12-14661078-C-T is described in ClinVar as Benign. ClinVar VariationId is 1592248.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00133 (203/152136) while in subpopulation AFR AF = 0.00453 (188/41504). AF 95% confidence interval is 0.004. There are 0 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004963.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2C	NM_004963.4	MANE Select	c.1283-16G>A		intron	N/A	NP_004954.2	P25092

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY2C	ENST00000261170.5	TSL:1 MANE Select	c.1283-16G>A		intron	N/A	ENSP00000261170.3	P25092
	GUCY2C	ENST00000867619.1		c.1283-16G>A		intron	N/A	ENSP00000537678.1
	GUCY2C	ENST00000970783.1		c.1283-16G>A		intron	N/A	ENSP00000640842.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000371 AC: 93 AN: 250516 AF XY: 0.000251

Gnomad AFR exome AF: 0.00481

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000165 AC: 228 AN: 1384772 Hom.: 1 Cov.: 24 AF XY: 0.000137 AC XY: 95 AN XY: 693248

African (AFR) AF: 0.00542 AC: 172 AN: 31728

American (AMR) AF: 0.000269 AC: 12 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25636

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39338

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000708 AC: 4 AN: 5646

European-Non Finnish (NFE) AF: 0.0000134 AC: 14 AN: 1041862

Other (OTH) AF: 0.000415 AC: 24 AN: 57896

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74396

African (AFR) AF: 0.00453 AC: 188 AN: 41504

American (AMR) AF: 0.000589 AC: 9 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67986

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000224 Hom.: 2

Bravo AF: 0.00138

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.91
DANN	Benign	0.54
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112926992; hg19: chr12-14814012;